Endocrine Abstracts

Background

SR141716 (Rimonabant) has been shown to significantly inhibit food intake and reduce body weight in rodents and humans by antagonising CB₁ receptors. The gut hormones peptide YY_3–36 (PYY_3–36) and oxyntomodulin (OXM), released from L-cells in the small intestine inhibit food intake in both rodents and humans and this effect is thought to be mediated via the hypothalamus.

Objective

To determine the effects of co-administration of SR141716 with either PYY_3–36 or OXM in mice on food intake.

Method

Mice (n=10 per group) fasted for 16 hours were given two intraperitoneal (i.p.) injections as described below:

Study 1: vehicle-saline, SR141716 (0.3 mg/kg)-saline, vehicle-PYY_3–36 (50 μg/kg) or SR141716-PYY_3–36.

Study 2: vehicle-saline, SR141716 (0.3 mg/kg)-saline, vehicle-OXM (1400 nmol/kg) or SR141716-OXM. Food intake was measured following injections.

Results

Co-administration of SR141716-PYY_3–36 resulted in a greater reduction in food intake when compared to administration of SR141716 or PYY_3–36 alone [Food intake 0–1 hr (g): vehicle-saline 0.97±0.04, SR141716-saline 0.87±0.05, vehicle-PYY_3–36 0.75±0.07, SR141716-PYY_3–36 0.52±0.06 (P<0.01 SR141716-PYY vs. SR141716-saline; P<0.01 SR141716-PYY vs. vehicle-PYY_3–36)]. Co-administration of SR141716 and OXM resulted in greater reduction in food intake when compared to administration of SR141716 or OXM alone [Food intake 0–1 hr (g): vehicle-saline 0.95±0.04, SR141716-saline 0.71±0.08, vehicle-OXM 0.68±0.06, SR141716-OXM 0.38±0.11 (P<0.01 SR141716-OXM vs. SR141716-saline; P<0.01 SR141716-OXM vs. vehicle-OXM)].

Conclusion

Our data shows that SR141716 in combination with PYY_3–36 or OXM reduces food intake additively in mice. In addition it is possible that combination therapy with SR141716 and PYY_3–36 or OXM may provide an effective therapy for obesity.